BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation

Fulgenzi, Gianluca; Tomassoni-Ardori, Francesco; Babini, Lucia; Becker, Jodi; Barrick, Colleen; Puverel, Sandrine; Tessarollo, Lino

doi:10.1085/jgp.1464oia55

Cited by 20 publications

(36 citation statements)

References 24 publications

(32 reference statements)

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“…Brain‐derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the mammalian central nervous system that promotes neuronal survival and differentiation . Growing studies have documented that BDNF plays crucial roles in the cardiovascular system . Among them, two recent studies proved that BDNF modulated the contraction of normal heart .…”

Section: Introductionmentioning

confidence: 99%

Brain‐derived neurotrophic factor attenuates doxorubicin‐induced cardiac dysfunction through activating Akt signalling in rats

Hang

Zhao

Sun

et al. 2016

J Cellular Molecular Medi

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The clinical application of doxorubicin (Dox) is limited by its adverse effect of cardiotoxicity. Previous studies have suggested the cardioprotective effect of brain‐derived neurotrophic factor (BDNF). We hypothesize that BDNF could protect against Dox‐induced cardiotoxicity. Sprague Dawley rats were injected with Dox (2.5 mg/kg, 3 times/week, i.p.), in the presence or absence of recombinant BDNF (0.4 μg/kg, i.v.) for 2 weeks. H9c2 cells were treated with Dox (1 μM) and/or BDNF (400 ng/ml) for 24 hrs. Functional roles of BDNF against Dox‐induced cardiac injury were examined both in vivo and in vitro. Protein level of BDNF was reduced in Dox‐treated rat ventricles, whereas BDNF and its receptor tropomyosin‐related kinase B (TrkB) were markedly up‐regulated after BDNF administration. Brain‐derived neurotrophic factor significantly inhibited Dox‐induced cardiomyocyte apoptosis, oxidative stress and cardiac dysfunction in rats. Meanwhile, BDNF increased cell viability, inhibited apoptosis and DNA damage of Dox‐treated H9c2 cells. Investigations of the underlying mechanisms revealed that BDNF activated Akt and preserved phosphorylation of mammalian target of rapamycin and Bad without affecting p38 mitogen‐activated protein kinase and extracellular regulated protein kinase pathways. Furthermore, the beneficial effect of BDNF was abolished by BDNF scavenger TrkB‐Fc or Akt inhibitor. In conclusion, our findings reveal a potent protective role of BDNF against Dox‐induced cardiotoxicity by activating Akt signalling, which may facilitate the safe use of Dox in cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Brain‐derived neurotrophic factor attenuates doxorubicin‐induced cardiac dysfunction through activating Akt signalling in rats

Hang

Zhao

Sun

et al. 2016

J Cellular Molecular Medi

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“…This aging phenotype might be involved in age‐related dysfunction of the angiogenic potential and other cardiac pathophysiology situations seen in aged hearts. Indeed, recent studies revealed that cardiomyocytes express both TrkB full‐length (TrkB‐FL) and TrkB‐T1 signalling, and both are likely required for the heart to fully contract and relax (Feng et al, ; Fulgenzi et al, ). However, the expression of TrkB‐T1 is significantly upregulated in failing heart (Feng et al, ).…”

Section: Discussionmentioning

confidence: 99%

The TrkB‐T1 receptor mediates BDNF‐induced migration of aged cardiac microvascular endothelial cells by recruiting Willin

Wang

Chen

et al. 2019

Aging Cell

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The mechanism of age‐related decline in the angiogenic potential of the myocardium is not yet fully understood. Our previous report revealed that the aging of cardiac microvascular endothelial cells (CMECs) led to changes in their expression of receptor Trk isoforms: among the three isoforms (TrkB‐FL, TrkB‐T1 and TrkB‐T2), only the truncated TrkB‐T1 isoform continued to be expressed in aged CMECs, which led to decreased migration of CMECs in aging hearts. Thus far, how BDNF induces signalling through the truncated TrkB‐T1 isoform in aged CMECs remains unclear. Here, we first demonstrated that aged CMECs utilize BDNF–TrkB‐T1 signalling to recruit Willin as a downstream effector to further activate the Hippo pathway, which then promotes migration. These findings suggest that the aging process shifts the phenotype of aged CMECs that express TrkB‐T1 receptors by transducing BDNF signals via the BDNF–TrkB‐T1–Willin–Hippo pathway and that this change might be an important mechanism and therapeutic target of the dysfunctional cardiac angiogenesis observed in aged hearts.

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“…CaMKII activation and recruitment to active zones depends on the intracellular increase in Ca 2+ levels, both through Ca 2+ channels, and Ca 2+ stores through the PLC and IP3 pathways [50,55]. In mammals, TrkB-T1 regulates Ca 2+ levels in glia and in the heart, two contexts expressing high levels of TrkB-T1 and no TrkB-FL [60-62]. However, the mechanism by which TrkB-T1 raises Ca 2+ is unknown [60,61], and whether this results in the activation of CaMKII is unclear or may be context dependent [60,62].…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, TrkB-T1 regulates Ca 2+ levels in glia and in the heart, two contexts expressing high levels of TrkB-T1 and no TrkB-FL [60-62]. However, the mechanism by which TrkB-T1 raises Ca 2+ is unknown [60,61], and whether this results in the activation of CaMKII is unclear or may be context dependent [60,62]. CaMKII activation in neurons could depend on the increase in Ca 2+ with neuronal activity.…”

Section: Discussionmentioning

confidence: 99%

KEK-6: A TRUNCATED-TRK-LIKE RECEPTOR FORDROSOPHILANEUROTROPHIN 2 REGULATES STRUCTURAL SYNAPTIC PLASTICITY

Ulian-Benitez

Bishop

Földi

et al. 2017

Preprint

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Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signalling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs) at the larval glutamatergic neuromuscular junction (NMJ). Starting with an unbiased approach, we tested the evelen LRR and Ig-containing (LIG) proteins encoded in the Drosophila genome for expression in the central nervous system (CNS) and potential interaction with DNTs. Kek-6 was expressed in the CNS, could interact genetically with DNTs and could bind DNT2 both in signaling essays and in co-immunoprecipitations. There is promiscuity in ligand binding, as Kek-6 could also bind DNT1, and Kek-5 could also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and binds DNT2 produced by the muscle, which functions as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth, bouton formation and active zone homeostasis. Kek-6 does not antagonise the alternative DNT2 receptor Toll-6, but rather the two receptors contribute in distinct manners to NMJ structural plasticity. Using pull-down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that together they regulate NMJ growth and active zone formation. These functions of Kek-6 could be evolutionarily conserved, raising the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk-family receptors independently of TyrK signaling may also operate in the human brain.AUTHOR SUMMARYA long-standing paradox had been to explain how brain structural plasticity, learning and long-term memory might occur in Drosophila in the absence of canonical Trk receptors for neurotrophin (NT) ligands. NTs link structure and function in the brain enabling adjustments in cell number, dendritic, axonal and synaptic patterns, in response to neuronal activity. These events are essential for brain development, learning and long-term memory, and are thought to depend on the tyrosine-kinase function of the NT Trk receptors. However, paradoxically, the most abundant Trk isoforms in the adult human brain lack the tyrosine kinase, and their neuronal function is unknown. Remarkably, Drosophila has kinase-less receptors of the Trk family encoded by the kekkon (kek) genes, suggesting that deep evolutionary functional conservation for this receptor class could be unveiled. Here, we show that Kek-6 is a receptor for Drosophila neurotrophin 2 (DNT2) that regulates structural synaptic plasticity via CaMKII and VAP33A, well-known factors regulating synaptic structure and plasticity, and vesicle release. Our findings suggest that in mammals truncated Trk-family receptors could also have synaptic functions in neurons independently of Tyrosine kinase signalling. This might reveal a novel mechanism of brain plasticity, with important implications for understanding also the human brain, in health and disease.

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BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation

Abstract: Abbreviations used in this paper: BDNF, Brain-derived neurotrophic factor; bpm, beats per minute; IP 3 , inositol-1,4,5-trisphosphate; LVDP, left ventricle developed pressure; PLB, phospholamban; WT, wild type.

Cited by 20 publications

References 24 publications

Brain‐derived neurotrophic factor attenuates doxorubicin‐induced cardiac dysfunction through activating Akt signalling in rats

Brain‐derived neurotrophic factor attenuates doxorubicin‐induced cardiac dysfunction through activating Akt signalling in rats

The TrkB‐T1 receptor mediates BDNF‐induced migration of aged cardiac microvascular endothelial cells by recruiting Willin

KEK-6: A TRUNCATED-TRK-LIKE RECEPTOR FORDROSOPHILANEUROTROPHIN 2 REGULATES STRUCTURAL SYNAPTIC PLASTICITY

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